One of the great mysteries in biology is how do certain animals regenerate lost body parts in response to trauma. Few examples of tissue regeneration exist in mammals, and studies of tissue regeneration in non- mammalian species are limited by a lack of molecular tools. This research plan aims to elucidate how mammalian tissue regeneration unfolds in a genetically defined mouse model of tissue regeneration. Aim #1 will determine the cellular basis of tissue regeneration utilizing developmental biology, lineage tracing, and conditional mouse genetics. Aim #2 will determine the role of a specific protein in regulating gene expression and chromatin accessibility during tissue regeneration. Aim #2 will utilize quantitative mRNA sequencing (RNA-Seq) and a new technique to footprint chromatin accessibility (ATAC-Seq). Successful completion of the proposed aims will greatly advance our understanding of how mammalian tissue regeneration unfolds, and this knowledge may offer insights on how to trigger tissue regeneration in humans and impact future strategies in regenerative medicine. This award will enable the principle investigator, a dermatology trained physician-scientist, to receive intensive training in skin biology, developmental biology, and genomics, and to develop an independent research program. Additionally, Dr. Leung will complete structured career development including didactic sessions, training in ethical conduct, and training in laboratory management. Stanford University is providing him full institutional support, extensive resources, and opportunity for collaborations with experts in the field. The Stanford Department of Dermatology has a strong track record in mentoring dermatology physician-scientists to independent positions. This award will help Dr. Leung transition to a full-time academic tenure-track position where he will spend 90% of his time on research and 10% on clinical activities.